All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Breast cancer is recognized as a collection of malignancies that all arise in the breast but are remarkably heterogeneous. Gene expression array experiments have defined at least 4 major subtypes: 1) Luminal A; 2) Luminal B; 3) HER2+; and 4) Basal. There is a strong correlation between clinically defined triple negative breast cancer “TNBC”, as defined by the absence of ER, PgR, and HER2 by standard immunohistochemical staining, and the molecularly defined basal subtype.
TN breast cancer accounts for only 10-15% of all incident breast cancer cases in the U.S., but results in a disproportionate number of breast cancer deaths. Women who are destined to develop metastatic TN disease typically experience a short disease free interval and have a higher degree of lung and brain involvement than patients with luminal breast cancers. Furthermore, TN breast cancer is overrepresented among patients who carry a deleterious BRCA1 germline alteration, and among women of African ancestry.
From a clinical perspective, despite substantial efforts to develop novel targeted agents, chemotherapy remains the mainstay of therapy for TN breast cancer, as trials evaluating a number of agents either in lieu of chemotherapy or in addition to chemotherapy have failed to produce any new agent that is capable of convincingly changing the natural history of the disease. In the adjuvant setting, polychemotherapy regimens have been demonstrated to improve both disease-free survival and overall survival. In the neoadjuvant setting, a favorable response to chemotherapy is associated with a low chance of relapse at 5 years. In contrast, women who have a significant amount of residual disease after a course of neoadjuvant chemotherapy have a particularly poor prognosis, with at least half experiencing a recurrence and death from TN breast cancer within 5 years. In the metastatic setting, although patients may respond to chemotherapy, the responses tend to be brief, and resistance tends to appear quickly.
Given the curative potential of chemotherapy in patients presenting with stage I-III TN breast cancer, and the initial responses (albeit often brief) seen with chemotherapy in the metastatic setting, the general direction of targeted therapy development for TN breast cancer has been to combine targeted agents with chemotherapy. Thus, even with a growing number of targeted therapies under investigation for TN breast cancer, chemotherapy is likely to be a significant component of the treatment of TN breast cancer for many years to come.
Across breast cancers as a whole, hormone receptor dependence and tumor proliferation appear to be associated with generic “chemosensitivity”. Using the 70 gene signature as an example, the current classifiers typically assign a “high-risk” status to the vast majority of TN tumors, and are also unable to define whether there may be differential benefit with one class of chemotherapeutic agents over another. Thus, in both clinical practice and in conventionally designed clinical trials, the tendency is to layer new therapies directly atop existing standards, increasing the risk of both overtreatment (because some, but not all of the administered therapies are efficacious) or undertreatment (because the tumor is not sensitive to any of the specific chemotherapeutic agents contained in the treatment regimen).
Accordingly, there exists a need in the art to identify the best chemotherapy for each patient and to eliminate agents that are inert and result in toxicity without benefit.